Altered action of angiotensin II in patients with type 2 diabetes mellitus of recent onset.
OBJECTIVE
Angiotensin II (Ang II) increases insulin sensitivity in healthy volunteers. This effect is thought to be mediated, at least in part, by an increase in skeletal muscle blood flow. In the past it had been documented that some biological actions of Ang II are altered in diabetes. We addressed the issue of whether this is also true for its action on insulin sensitivity.


METHODS
Twelve healthy volunteers (aged 43+/-9 years) and 15 patients with type 2 diabetes mellitus (NIDDM) of recent onset (aged 45+/-9 years) were allocated in random order in a double-blind placebo-controlled design to be administered a sham infusion or an infusion of 2 ng Ang II/kg per min. Insulin-stimulated glucose uptake (the M value) was measured with the euglycaemic clamp technique, leg muscle blood flow (MBF) with plethysmography, blood pressure with a Dinamap device, and glomerular filtration rate and effective renal plasma flow with the steady-state inulin (Cin) and p-aminohippurate (CPAH) clearance methods, respectively.


RESULTS
In volunteers the mean M-value after Ang II infusion (10.1+/-1.5 mg/kg per min) was significantly higher (P < 0.01) than that after sham infusion (8.2+/-0.9 mg/kg per min). In contrast, in diabetic patients it was not significantly different with Ang II (6.1+/-1.3 mg/kg per min) and sham infusion (5.5+/-1.2 mg/kg per min). The difference in the mean absolute increase in the M value (deltaM) between groups was significant (P< 0.02). The Ang II-induced increase in MBF under euglycaemic conditions was attenuated in diabetic patients (from 15.0+/-3.5 to 15.5+/-3.9 ml/100 ml per min, NS) compared with volunteers (from 16.8+/-3.3 to 19.1+/-3.7 ml/100 ml per min, P< 0.01). Again, the difference between the mean absolute increases in MBF (deltaMBF) in the groups was significant (P < 0.01). A significant correlation was found between deltaMBF and deltaM (r= 0.62, P<0.01). The absolute acute increase in mean arterial blood pressure with Ang II was similar in diabetic patients and volunteers. Mean Cin, CPAH and fractional sodium excretion values were significantly lower and renal vascular resistances and filtration fractions higher during the Ang II than they were during the placebo clamp period. This was observed in patients as well as in healthy subjects, but the effects of Ang II on renal haemodynamics and sodium handling were more pronounced in diabetic patients.


CONCLUSIONS
In patients with NIDDM of recent onset the stimulatory effect of Ang II on insulin sensitivity and on skeletal muscle blood flow is attenuated. In contrast, the effects of Ang II on renal perfusion and sodium handling are more pronounced in patients with NIDDM than they are in healthy subjects.
Fliser
D
D
Department of Internal Medicine, Ruperto-Carola University, Heidelberg, Germany.
Keller
C
C
Bahrmann
P
P
Franek
E
E
Schreckling
H
H
Bergis
K
K
Ritz
E
E
D000328:Adult; D000804:Angiotensin II / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004311:Double-Blind Method; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007328:Insulin; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000098:blood supply; D012016:Reference Values; D012039:Regional Blood Flow / Q000187:drug effects; D012079:Renal Circulation / Q000187:drug effects; D012964:Sodium / Q000378:metabolism
D007328:Insulin; D000804:Angiotensin II; D012964:Sodium